CN111920446A

CN111920446A - System for enhancing medical treatment using ultrasound

Info

Publication number: CN111920446A
Application number: CN201910676496.7A
Authority: CN
Inventors: 张吉民; 李彤
Original assignee: Individual
Current assignee: Individual
Priority date: 2019-05-13
Filing date: 2019-07-25
Publication date: 2020-11-13

Abstract

A system for enhancing medical therapy using ultrasound includes an ultrasound imaging display, a therapy monitoring display, a robotic arm, a transducer module, a drug delivery unit, and an ultrasound engine control system. When the ultrasonic engine control system is used, the real-time controller of the computing unit of the ultrasonic engine control system controls the mechanical arm to drive the transducer module to move to a target position, the drug delivery unit delivers drugs to the target position and the transducer module delivers treatment ultrasonic energy to the target position synchronously, the transducer module can transmit the obtained target ultrasonic imaging information and the monitored cavitation state of each target to the ultrasonic engine control system, and the ultrasonic engine control system can adjust the treatment position at any time according to the information. The ultrasonic engine control system controls the transducer module to deliver the therapeutic ultrasonic energy to the target and synchronously controls the drug delivery unit to deliver the required drug amount to the target, and the therapeutic ultrasonic energy enhances the absorption effect of the drug delivered to the focus.

Description

System for enhancing medical treatment using ultrasound

The present application claims priority from the united states patent office filed on 2019, 05/13, application No. 62/847253 entitled "system and method for enhancing medical treatment using ultrasound" which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to a non-invasive system for applying ultrasound energy for therapy through real-time ultrasound imaging guidance based on cavitation monitoring, robotic arms, and energy feedback control loops, and more particularly to a system for enhancing medical therapy using ultrasound.

Background

A plurality of international scientific research achievements show that the combined use of cancer immunotherapy, chemotherapy and focused ultrasound therapy greatly improves the life quality of cancer patients, reduces the nursing cost, reduces the system toxicity response caused by chemotherapy, improves the effective intake of medicines and prolongs the life. However, current techniques and devices for drug delivery merely deliver the drug to the target lesion tissue and the drug is not well absorbed by the lesion.

Therefore, how to enhance the effect of the drug delivered to the lesion is a technical problem to be solved urgently by those skilled in the art.

Disclosure of Invention

In view of the above, it is an object of the present invention to provide a system for enhancing medical treatment using ultrasound to enhance the effect of drugs delivered to a lesion.

The present invention provides a system for enhancing medical treatment using ultrasound, comprising:

an ultrasound imaging display capable of displaying anatomical ultrasound imaging of a subject;

a treatment monitoring display capable of displaying anatomical ultrasound imaging of the target, a cavitation state of the target, and location information of the target in real-time;

a robotic arm that is free to move in space;

a transducer module configured at the distal end of the robotic arm to move along the targets, wherein the transducer module is capable of delivering therapeutic ultrasound energy to the locations of the targets, detecting the locations of the targets, obtaining ultrasound imaging information of the targets, and monitoring a cavitation status of each of the targets;

a drug delivery unit capable of delivering a therapeutic agent and/or an ultrasound contrast agent to the target, wherein the drug delivery unit delivers in synchrony with therapeutic ultrasound energy from the transducer module; and

an ultrasound engine control system comprising a computing unit real-time controller, wherein the computing unit real-time controller controls the motion of the robotic arm, controls the delivery of therapeutic ultrasound energy from the transducer module, and processes the cavitation status and spatial position of the transducer module received by the anatomical ultrasound imaging from the transducer module for anatomical ultrasound imaging real-time display of the target, target position tracking motion compensation, cavitation monitoring, ultrasound energy output control, and delivery of drug doses and delivery control of the drug delivery unit.

In a particular embodiment, the transducer module includes separate transducer elements for each function, including a therapy transducer, an imaging transducer, and one or more broadband receiving sensors.

In another particular embodiment, the transducer module includes a single multi-functional transducer array integrated with the functions of transmitting therapeutic ultrasound energy, detecting a target location, and monitoring cavitation conditions from the respective transducer elements.

In another specific embodiment, the transducer module further comprises a frame surrounding the transducer elements.

In another specific embodiment, the transducer module is removably mounted on a robotic arm.

In another specific embodiment, the robotic arm has six degrees of freedom of motion.

In another specific embodiment, the transducer module sends a signal to the ultrasound engine control system via a cable line or wirelessly.

In another specific embodiment, the number of said mechanical arms is 2, one of said mechanical arms is equipped with said treatment transducer, the other of said mechanical arms is equipped with said imaging sensor and 1 or more of said broadband receiving transducers.

In another specific embodiment, the number of said mechanical arms is 3, one of said mechanical arms is equipped with said treatment transducer, one of said mechanical arms is equipped with said imaging transducer, and the other of said mechanical arms is equipped with 1 or more broadband receiving transducers.

In another specific embodiment, the system further comprises an interface through which movement of the robotic arm is controlled to enable remote control of the system, the interface capable of providing image data to a location of the remote control.

In another specific embodiment, the anatomical ultrasound imaging is a 3D reconstructed image from a B-mode image or a plurality of ultrasound images.

In another specific embodiment, the imaging from the treatment monitoring display is a 1D map showing the change in cavitation status over time, and/or a 2D map of the cavitation status overlaid on the anatomical ultrasound imaging.

In another specific embodiment, the therapeutic transducer is capable of generating pulses for inducing steady-state or inertial cavitation with or without the ultrasound contrast agent.

In another specific embodiment, the imaging transducer receives pulses for the anatomical ultrasound imaging.

In another specific embodiment, the broadband receiving sensor receives pulses for cavitation monitoring or cavitation imaging.

In another specific embodiment, the ultrasound engine control system further comprises a robotic arm spatial position control subsystem under control of a dose plan calculation timing control module contained within the computational unit real-time controller to control spatial motion of the robotic arm.

In another specific embodiment, the ultrasound engine control system further comprises an ultrasound imaging target tracking subsystem, wherein the ultrasound imaging target tracking subsystem receives the anatomical ultrasound imaging from the transducer module of each target location and transmits to the computing unit real-time controller.

In another specific embodiment, the calculation unit real-time controller comprises a 3D image registration reconstruction module and the dose plan calculation delivery timing control module.

In another specific embodiment, the 3D image registration reconstruction module reconstructs a 3D volumetric image of the target using ultrasound imaging of each target location and corresponding spatial location of the transducer module.

In another specific embodiment, the dose plan calculation delivery timing control module processes target locations of the target and 3D volumetric images and sends motion compensation signals to the robotic arm spatial location control subsystem for motion compensation at each of the target locations.

In another specific embodiment, the ultrasound engine control system further comprises a cavitation therapy monitoring subsystem to provide real-time monitoring of cavitation status as an input to the dose plan calculation delivery time series, the control module generating a dose compensation plan and a delivery time series, wherein the cavitation therapy monitoring subsystem receives cavitation status signals from the transducer module at each of the target locations.

In another specific embodiment, the dose compensation plan delivery time series is generated by overlaying the cavitation state input for each target location onto the ultrasound imaging for each of the target locations.

In another particular embodiment, the ultrasound engine control system further comprises an ultrasound therapy subsystem, wherein the ultrasound therapy subsystem controls the transducer module to deliver therapeutic ultrasound energy.

In another specific embodiment, the ultrasound engine control system comprises a drug delivery control subsystem, wherein the drug delivery control subsystem controls the drug delivery unit to deliver the therapeutic agent and/or the ultrasound contrast agent.

In another particular embodiment, the dose compensation plan and the delivery time sequence generated from the dose plan calculation delivery timing control module instruct the ultrasound therapy subsystem to adjust the dose and delivery time of therapeutic ultrasound and instruct the drug delivery control subsystem to adjust the dose and delivery time of the therapeutic agent and/or the ultrasound contrast agent.

The various embodiments according to the invention can be combined as desired, and the embodiments obtained after these combinations are also within the scope of the invention and are part of the specific embodiments of the invention.

The invention provides an excellent and easy-to-use noninvasive system for enhancing drug delivery to a focus by utilizing ultrasound, when in use, a computing unit real-time controller of an ultrasound engine control system controls a mechanical arm to drive a transducer module to move to a target position, a drug delivery unit delivers drugs to the target position and the transducer module delivers treatment ultrasonic energy to the target position synchronously, the transducer module can transmit obtained target ultrasonic imaging information and monitored cavitation states of each target to the ultrasound engine control system, and the ultrasound engine control system can adjust the treatment position at any time according to the information. The ultrasonic engine control system controls the transducer module to deliver the therapeutic ultrasonic energy to the target and synchronously controls the drug delivery unit to deliver the required drug amount to the target, and the therapeutic ultrasonic energy enhances the absorption effect of the drug delivered to the focus.

The system non-invasively delivers a defined amount of ultrasound energy at a treatment location (e.g., cancerous tissue) in 3D space with assistance from a robotic arm, and provides a feedback control loop of acoustic energy based on cavitation monitoring at the target region. The system makes patient treatment more effective by compensating tissue characteristics for changes in treatment location (e.g., depth) and movement of the treatment location due to patient breathing or other motion during treatment. Depending on the system configuration, clinical indication and therapeutic target, the ultrasound energy may have a high intensity, a medium intensity, a low intensity, or a combination of intensities. The therapeutic agent may be microparticles with a gas core, or a drug mixed with an ultrasound contrast agent to enhance ultrasound cavitation and drug binding. The present system utilizes images and robotic arms to track treatment locations in real time and automatically move transducer modules attached to the ends of the robotic arms to deliver fine tuned acoustic energy to the treatment locations (e.g., tumors). The present application greatly simplifies operations and processing procedures and reduces processing time and costs.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. It is obvious that the drawings in the following description are only examples of the invention, from which other embodiments of the invention can be derived without inventive effort for a person skilled in the art.

Fig. 1A-1B depict two exemplary systems of the present invention for targeted drug delivery and therapeutic enhancement. Which illustrate different mounting orientations of the robotic arm relative to the clinician and patient. The ultrasound system includes real-time ultrasound imaging and a robotic arm to direct focused ultrasound energy to a target location in the abdominal region of a patient through drug delivery. Reference numeral 100 depicts a system for ultrasound enhanced drug delivery, reference numeral 101 depicts a patient, reference numeral 102 depicts a bed, reference numeral 103 depicts an ultrasound engine control system, reference numeral 104 depicts an ultrasound imaging display, reference numeral 105 depicts a display and location for therapy and cavitation monitoring, reference numeral 106 depicts a robotic arm, reference numeral 107 depicts a transducer module connected at the end of the robotic arm, and reference numeral 108 depicts a unit for drug delivery.

Fig. 2 depicts the main functional block diagram and architecture of the present invention. Reference numeral 201 depicts a drug delivery control subsystem that provides a defined dose of therapeutic drug and ultrasound contrast agent (microbubbles) to a patient, reference numeral 202 depicts an ultrasound therapy subsystem, reference numeral 203 depicts a cavitation therapy monitoring subsystem, reference numeral 204 depicts an ultrasound imaging target tracking subsystem, reference numeral 205 depicts a treatment volume transducer module spatial position control subsystem (also referred to herein as a "mechanical arm spatial position control subsystem"), reference numeral 206 depicts a 3D image registration and reconstruction module, reference numeral 207 depicts a dose plan calculation delivery timing control module, and reference numeral 108 depicts elements of an exemplary drug delivery.

FIG. 3 depicts an exemplary diagram of the main functional and control blocks within the compute unit real time controller 200 and their interconnections to the subsystems. The computing unit real time controller 200 has the capability to deliver a defined dose of drug and ultrasound output energy to a target location within the patient's body while monitoring the cavitation state and spatial location of the target and serving as feedback and ultrasound output energy to control the drug dose.

Fig. 4 depicts an exemplary configuration of control and interconnection between the drug delivery control subsystem 201 and the drug delivery unit 108.

Fig. 5 depicts an exemplary functional diagram of an ultrasound therapy subsystem 202 connected to a therapy transducer 219 to generate therapeutic ultrasound for medical therapy.

Fig. 6 depicts an exemplary functional diagram of the cavitation therapy monitoring subsystem 203 and its interconnection with the broadband reception sensor 218.

Fig. 7A-7B depict two exemplary configurations of the transducer module 107, including a frame 230, an ultrasound imaging transducer 231, a therapy transducer 219, and one or more broadband receiving sensors 218 for cavitation monitoring. Fig. 7A depicts an exemplary transducer module 107 in which an imaging transducer 231 and a separate therapy transducer 219 are located within a transducer frame 230, with a plurality (e.g., 8) of broadband transducers 218 (e.g., PVDF broadband transducers) surrounding the imaging transducer 231 for cavitation monitoring. Figure (a). Fig. 7B depicts another exemplary transducer module 107 in which a single transducer array 220 is used for imaging, therapy, and cavitation detection. The multifunctional transducer may be a one-dimensional linear/phased array or a two-dimensional array.

Fig. 8 depicts an exemplary configuration of a display for treatment, cavitation monitoring and location. In the upper part of the display it shows an ultrasound B-mode image of the tissue, wherein the predetermined treatment location is covered to cover the area to be treated. During treatment, a cavitation detection map is also overlaid on the B-mode image. A measure of cavitation dose is shown on the upper right side of the display, with a steady state cavitation threshold and an inertial cavitation threshold. In the lower half of the display, the desired treatment position, either automatically determined by the dose planning calculation or manually determined by the clinician, is overlaid on the 3D reconstructed volumetric image. The treatment progress is displayed in real time in the lower right.

FIG. 9 depicts an exemplary configuration of a linear transformation of an expected target position [ Ixi, Iyi ] located by ultrasound imaging and a current target position [1xj, Iyj ] detected by cavitation monitoring of the base coordinates or global coordinates of the mechanical arm.

Detailed Description

In order to make the technical solutions of the present invention better understood, the present invention will be further described in detail with reference to the accompanying drawings and specific embodiments.

The terms used in this disclosure have their conventional meanings in the art to which they pertain. Definitions of several terms are given herein in the present disclosure. If the conventional meaning of the term is inconsistent with the definitions herein, the definitions herein control.

The terms "1D", "2D", "3D", "4D", "5D", "6D", etc. denote one, two, three, four, five, six, etc. dimensions.

The term "Ultrasound Contrast Agent (UCA)" as used herein refers to a microbubble contrast agent for ultrasound imaging that enhances ultrasound backscatter (reflection) of ultrasound waves, resulting in an ultrasound image with increased contrast due to its high echogenicity in the blood stream, which can improve the visual contrast of the blood stream with respect to surrounding tissue. These micron-sized particles comprise a gas core surrounded by a micro-shell, which may be composed of albumin, galactose, lipids or polymers, and injected into the circulatory system by intravenous injection.

The term "B-mode imaging" means a two-dimensional ultrasound image consisting of bright spots representing ultrasound echoes. The brightness of each point may be determined by the amplitude of the returned echo signal. This allows visualization and quantification of anatomical structures, as well as imaging of diagnostic and therapeutic procedures for small animal studies.

The terms "coupled," "connected," and "associated" generally mean electrically, electromagnetically, and/or physically (e.g., mechanically or chemically) coupled or linked, and do not preclude the presence of intermediate elements in the coupling or linking. There are no related items in a particular opposite language.

The terms "program" or "software" are used herein in a generic sense to refer to any type of computer code or set of computer-executable instructions that can be employed to program a computer or other processor to implement various aspects. As noted above, in addition, it should be appreciated that according to one aspect, one or more computer programs that when executed perform the methods of the present application need not reside on a single computer or processor, but may be distributed in a modular fashion amongst a number of different computers. Or a processor to implement various aspects of the present application.

The term "intended treatment location" is used to describe the location to be treated, which is manually selected by the clinical operator from the ultrasound image or automatically calculated from the dosimeter.

The term "current treatment position" is used to describe the position to which ultrasound energy is delivered. This position can determine the current treatment position from the cavitation map. The center of the cavitation zone is defined as the current treatment location. At any time, when cavitation occurs, the current treatment location will be recorded. Ideally, the current treatment position overlaps with the intended treatment position, but may deviate from the intended treatment position due to variations in tissue motion, system control accuracy, and tissue non-uniformity properties. The current treatment position is detected by real-time imaging and used as control feedback for robot spatial position adjustment and treatment ultrasound energy delivery. Spatial motion of the intended treatment location is compensated for by the ultrasound imaging and target tracking subsystem to update the current treatment location, as well as to compensate for system controls and other changes in tissue characteristics.

The term "spatial position" is used to describe the position of a treatment module attached to the distal end of a robotic arm, which may be updated and optimized by a robotic arm spatial position control subsystem

It should also be noted that the singular forms, such as the term "transducer" is intended to mean a single transducer or a combination of transducers, and "fluid" is intended to mean one or more fluids or mixtures. Furthermore, the words "proximal" and "distal" refer to directions in which the physician is closer to and away from, respectively, the operating device, with the transducer placed on top of the patient's body.

It is to be understood that embodiments of the present application described herein include embodiments that "consist of and/or" consist essentially of.

References herein to a "value or parameter of" about "includes (and describes) variations that are directed to that value or parameter itself. For example, a description referring to "about X" includes a description of "X".

As used herein, references to "non" values or parameters generally mean and describe "in addition to" the value or parameter. For example, the method is not used to treat type X cancer, meaning that the method is used to treat other types of cancer other than X.

The term "about X-Y" as used herein has the same meaning as "about X to about Y".

As used herein and in the appended claims, the singular forms "a," "or," and "the" include plural referents unless the context clearly dictates otherwise.

The following detailed description refers to the accompanying drawings. The drawings, which are not necessarily to scale, illustrate the principles of the invention in the detailed description and are not intended to provide actual dimensions of the components in the system. The description will enable one of ordinary skill in the art to make and use the invention, and describes several embodiments, adaptations, alternatives and uses.

It should be understood that the present invention is not limited to use in the human body unless otherwise specified. Although reference is made herein to human patients, one of ordinary skill in the art will recognize that the variants of the invention are also applicable to other animals, such as mammals. Moreover, it should be understood that embodiments of the present invention may be applied to the delivery of ultrasonic energy to a patient for therapeutic and/or diagnostic purposes. Drug delivery to enhance treatment of pancreatic cancer is provided herein as an example of clinical application. One of ordinary skill in the art having benefit of the present disclosure will appreciate that variations and embodiments of the present invention may be applied to different clinical applications and indications, including but not limited to neuromodulation, tissue ablation, cancer treatment, tissue activation, tissue heating, tissue degeneration, drug activation, and immunotherapy. The disclosed apparatus and systems should not be construed as limiting in any way. Rather, the present disclosure is directed to all novel and nonobvious features and aspects of the various disclosed embodiments, alone and in various combinations and subcombinations with one another. The apparatus and systems are not limited to any specific aspect or feature or combination thereof, nor do the disclosed embodiments require that any one or more specific advantages be present or problems be solved

Another aspect of the present application provides for the operation of some of the disclosed embodiments to be described in a particular order for convenient presentation, it being understood that this manner of description encompasses rearrangement, unless a particular ordering is specifically required. The following language is used, for example, to describe the operations sequentially and in some cases may be rearranged or performed concurrently.

Further provided are only certain selected aspects of the system architecture, controller diagram, clinical application, program/software-based implementation of the present application. For example, it should be understood that the disclosed technology is not limited to any particular ultrasound imaging system or implemented computer language or program. In some embodiments, the present invention provides programs and software configured to perform any of the system/subsystem functions described above.

The present application describes various embodiments of systems and methods for delivering ultrasound energy via a robotic arm, optionally in combination with a therapeutic agent.

The present application provides a system 100 for enhancing medical therapy using ultrasound that can perform 3D volumetric medical therapy, such as cancer therapy, in which real-time cavitation status monitoring is used as a feedback control of the targeted delivered amount of ultrasound energy to provide the patient with an acoustic energy dose of the same or similar amount throughout the treatment region (e.g., tumor). The system 100 also monitors treatment location in real time using intelligent motion tracking methods based on ultrasound imaging to provide real-time compensation for changes in treatment dosage and location due to differences in patient tissue characteristics and organ motion.

The system provided herein can eliminate the time required for an operator to locate a treatment location, moving the treatment module to target different locations within the patient to cover the entire volume to be treated to reduce the treatment time and labor of the operator, thereby reducing treatment complexity and cost.

Due to differences in target depth, tissue characteristics, tissue motion, etc., the system 100 described herein can adjust the acoustic energy intensity and dose tailored to the cavitation threshold of each patient. The ultrasound engine controls the customized treatment plan 103 that the system automatically generates, according to the shape of the tumor.

The system 100 described herein ensures fully automated treatment with the motion of the robotic arms throughout the treatment process. The system 100 determines the treatment dosage based on the desired treatment depth within the patient (see fig. 2, 3), and a transducer module 107 included in the ultrasound probe is used to monitor the cavitation condition while providing ultrasound energy treatment. The spatial position of the transducer module 107 is controlled by the robotic arm 106 to precisely target the desired treatment location. The robotic arm 106 follows the movement of the intended treatment location according to tracked target position information of the ultrasound imaging captured by the imaging transducer within the transducer module 107 and processed by the ultrasound imaging target tracking subsystem 204 so that the treatment location is unaffected by the movement displacement at the intended treatment location

In some embodiments, the system 100 described herein is configured with one or more robotic arms (e.g., 106 in the figures) to meet a desired degree of freedom of motion, such as 1D, 2D, 3D, 4D, 5D, 6D or more degrees of freedom of motion. In some embodiments, one or more robotic arms are interconnected through a compute unit real time controller (CURC)200 to communicate spatial locations to other subsystems. In some embodiments, one or more robotic arms are used to track the motion of the same intended treatment location and adjust their spatial position based on the motion tracking information.

In some embodiments, the ultrasound energy may have a high intensity, a medium intensity, a low intensity, or a combination of these intensities, depending on the system configuration, clinical indication, and therapeutic target. In some embodiments, the ultrasound energy is delivered through an ultrasound probe, which includes a transducer module 107.

In some embodiments, the transducer module 107 includes a therapy transducer 219 that outputs ultrasound energy for therapeutic purposes. In some embodiments, the transducer module 107 includes an imaging transducer 231 that outputs ultrasound energy for imaging purposes. For example, the imaging transducer receives pulses for B-mode imaging, which can be used for current treatment location detection, tissue motion tracking, and cavitation detection. In some embodiments, the transducer module 107 includes one or more broadband receiving sensors 218 that obtain acoustic cavitation information and send back to control the energy output of the system 100.

In some embodiments, the medical drug delivered in combination with ultrasonic energy is a microparticle having a gas-like core or shell. In some embodiments, the medical drug is mixed with an ultrasound contrast agent to enhance ultrasound cavitation and drug action.

In some embodiments, the system 100 described herein is configured to deliver ultrasound energy in one or more treatment volumes within an individual using a transducer module. In some embodiments, the subject is an animal, including but not limited to animals such as monkeys, cows, pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal, most preferably a human.

In some embodiments, the ultrasound imaging or signals may be used to track the position of the treatment volume and maintain the focus of the ultrasound energy field within a cross-section of the 3D treatment volume during the treatment period.

In some embodiments, the system 100 described herein is configured during ultrasonic energy delivery to monitor the treatment status at a particular treatment location or locations, e.g., the onset of steady state cavitation, the onset of inertial cavitation, or the onset of a boiling state. For example, in some embodiments, the system includes a cavitation therapy monitoring subsystem 203 that receives and processes cavitation signals detected by the transducer module 107.

In some embodiments, the system 100 described herein is configured to automatically calculate and adjust the system 100 settings to deliver a defined amount of ultrasound energy dose at a particular or multiple treatment locations based on the cavitation status detected by the cavitation therapy monitoring subsystem 203. For example, in some embodiments, the system 100 described herein is configured to automatically adjust the system 100 settings to increase or decrease the amount of ultrasound energy applied by the ultrasound therapy subsystem 202 via a particular treatment location or locations until the onset of certain steady-state or inertial cavitation is detected by the cavitation therapy monitoring subsystem 203, by values calculated by the dose plan calculation timing control module 207. For example, in some embodiments, stable cavitation is detected by extracting stable cavitation from the harmonic signals of the RF signals received during monitoring of the treatment. Inertial cavitation is detected by extracting broadband noise between harmonic signals from the RF signal received by the therapy monitoring subsystem 203. The occurrence of sub-harmonic signals and the occurrence of broadband noise in the received RF signal are defined as a stable cavitation threshold and an inertial cavitation threshold, respectively. The detected cavitation conditions at the treatment location are used to control the ultrasound dose or energy output relative to defined steady-state cavitation and inertial cavitation thresholds. For example, if steady state cavitation is desired to enhance drug delivery while eliminating the possibility of any tissue damage due to thermal and inertial cavitation, the cavitation conditions are controlled between defined steady state and inertial cavitation threshold limits. If the system detects a cavitation condition between the steady state and inertial cavitation thresholds, the same dose should be used. In some embodiments, when the detected cavitation condition at the target is below a defined threshold limit, more dose compensation will be calculated and planned by the dose plan calculation timing control module 207 and the increased amount of ultrasound energy is delivered to the current treatment position of the treatment transducer 219 and controlled by the ultrasound treatment subsystem 202. In some embodiments, when the detected cavitation condition at the current treatment position is above a defined threshold limit, a lower dose will be calculated and planned by the dose plan calculation timing control module 207, delivered by the treatment transducer 219 and controlled by the ultrasound therapy subsystem 202.

In some embodiments, the system 100 is configured to automatically adjust system settings to deliver defined amounts of ultrasound energy at a particular or multiple treatment locations, regardless of variations in treatment depth and individual treatment locations, such as tumor type and number.

In some embodiments, during ultrasound delivery, the computational unit real-time controller subsystem 200 within the system 100 described herein is configured to evaluate the results (e.g., cavitation intensity) from the cavitation therapy monitoring subsystem 203 in real-time to provide inputs to the dose plan calculation timing control module 207 to process calculations of real-time microbubble and/or therapeutic drug doses and adjustments of ultrasound energy. The ultrasound therapy subsystem 202 then delivers the newly calculated ultrasound energy for the particular treatment location or locations and the drug delivery control subsystem 201 delivers the newly calculated doses of microbubbles and/or therapeutic drugs. See, for example, fig. 3.

In some embodiments, the ultrasound imaging target tracking subsystem 204 is configured to automatically track movement of the treatment location, e.g., organ motion due to patient breathing or body motion during treatment, capturing real-time ultrasound images and ultrasound signals obtained from the transducer module 107 in real-time. In some embodiments, automatic motion tracking is used to track specific treatment locations. In some embodiments, automatic motion tracking is used to track multiple treatment positions. See, for example, fig. 3.

In some embodiments, the robotic arm spatial position control subsystem 205 is configured to automatically control the position and movement of the robotic arm 106 in real-time so as to compensate for the spatial motion (Δ Xi, Δ Yi, Δ Zi) of the current treatment position. Wherein the tracking motion information of the predicted treatment position (Xi, Yi, Zi) is obtained from the ultrasound imaging target tracking subsystem 204 and calculated by the calculation unit real-time controller subsystem 200. In some embodiments, the ultrasound imaging target tracking subsystem 204 provides the current treatment location information (Xj, Yj, Zj) as an input to the dose plan calculation timing control module 207. In some embodiments, an ultrasound image target tracking subsystem 204 acquired by ultrasound imaging is used as an input to the 3D image registration reconstruction module 206, along with a corresponding spatial position (rx, ry, rz, Φ x, Φ y, Φ z) control subsystem 205 for the transducer module 107 obtained from the spatial position of the robotic arm. rx, ry and rz are the translational positions and Φ X, Φ Y, Φ Z are the rotational angular positions of the therapy module in the mechanical arm coordinates about the X, Y, Z axes, respectively. The robot coordinate center is defined at the center of the robot base and is mounted on the solid object most of the time. The imaging transducer 231, therapy transducer 219, and broadband transducer 218 within the transducer module 107 may be the same or separate two or separate three objects. See, for example, figure. The spatial transformation from the transducer 231,219 or 218 to the transducing acoustic module 107 is fixed and does not change once the transducing acoustic module 107 is manufactured and calibrated. For any position [ Ix, Iy ] detected by the imaging transducer 231, its spatial position in the robot arm coordinates can be determined by the following equation

Wherein R is a rotation matrix from the transducer module to the mechanical arm coordinates, which can be determined according to rotation angles Φ x, Φ y, and Φ z; ta and Ra are translation and rotation matrices from the imaging transducer 231 to the transducer module 107, respectively. Once the transducer module 107 is manufactured, Ta and Ra may be determined by calibration.

For example, the operator selects the desired treatment location (Ixi, Iyi) on a cross-sectional image of the patient's body detected by the imaging transducer 231. The spatial position of the desired treatment position in the robot arm coordinates may be determined by:

here, the number of the first and second electrodes,

if the same imaging transducer 231 is used for cavitation or therapy monitoring, the detected current therapy position occurs at a cross-sectional image of the patient's body (Ixj, Iyj). The spatial position of the current treatment position in the robotic arm coordinates may be determined by:

the difference in spatial position is the change in distance from the current treatment position to the intended treatment position in X, Y and Z coordinates. In some embodiments, the difference in spatial position (Δ Xi, Δ Yi, Δ Zi) may be used for spatial motion compensation tracked and calculated by the tracking algorithm.

ΔP_i＝P(x_j，y_j，z_j)-P(x_i，y_i，z_i)＝(Δx_i，Δy_i，Δz_i)＝(x_j，x_i，y_j-y_i，z_j-z_i)

In some embodiments, the 3D image registration reconstruction module 206 processes the input signals to construct a 3D volumetric image that is converted for dose plan calculation and delivers a time series control module 207 to define a treatment plan in 3D space. See, for example, fig. 3.

In some embodiments, the computational unit real-time controller 200 is configured to integrate target tracking output parameters, such as the desired treatment location (Xi, Yi, Zi) from the ultrasound imaging target tracking subsystem 204, the monitored cavitation status from the cavitation treatment monitoring subsystem 203, to provide real-time control of the ultrasound output energy of the ultrasound treatment subsystem 202, maintain the ultrasound energy focus at the desired treatment location throughout the treatment by the robotic arm spatial position control subsystem 205 (controlling the robotic arm 106), and adjust the delivery time and dose of the therapeutic drug and ultrasound contrast agent (e.g., microbubbles) by the drug delivery control subsystem 201 (which controls the drug delivery unit 108). See, for example, fig. 3.

In some embodiments, the transducer module 107 is used for 2D/3D imaging scanning, ultrasound energy delivery, or a combination thereof to track specific intended treatment locations and direct ultrasound energy delivery to those locations during treatment. In some embodiments, the ultrasound delivery is performed by a therapy transducer, such as a 2D/1D array or a single element transducer. In some embodiments, one or more broadband receiving sensors or arrays of broadband receiving sensors are also included within the transducer module 107 to monitor cavitation conditions.

In some embodiments, the transducer for imaging and target tracking (e.g., 231), the transducer for cavitation detection (e.g., 218), and the transducer for ultrasound energy delivery (e.g., 219) may be integrated into one, two, or any combination of three sensor modules. For example, depending on the clinical application and design configuration of the transducer module, one transducer module may be used for imaging and therapy (e.g., including the imaging transducer 231 and the therapy transducer 219), while one or more separate transducers are used for cavitation monitoring (e.g., the broadband reception sensor 218). In some embodiments, the multifunctional transducer array 220 may have the functionality of integrating 2D/3D scanning, ultrasound energy delivery, and cavitation monitoring (e.g., the multifunctional transducer array 220 in fig. 7B). In some embodiments, the system 100 described herein may include two robotic arms, a first robotic arm configured with a first transducer module including a therapy transducer, a second robotic arm configured with a second transducer module including an imaging transducer and one or more broadband receiving sensors. In some embodiments, a system described herein may include three robotic arms, a first robotic arm configured with a first transducer module including a therapy transducer, a second robotic arm configured with a second transducer module including an imaging transducer, and a third robotic arm configured with a third transducer module including one or more broadband receiving sensors. In some embodiments, the ultrasound engine control system 103 directs the transducer module 107 to send signals over a cable link or wirelessly.

In some embodiments, the center of the tumor region is set by the operator or clinician on the ultrasound imaging display 104 by clicking a mouse with a mouse pointer at the center of the tumor, or by touching the tumor center with a touch screen, or by pressing a button on the transducer module 107 to record the center position when the defined position is at the center of the tumor as shown on the ultrasound imaging display 104. This set position is the initial position of the treatment position.

In some embodiments, each time a tumor region is visualized on the ultrasound imaging display 104, the operator/clinician clicks a button on the robotic arm 106 or on the transducer module 107, then an ultrasound image (Ii) is acquired by the ultrasound imaging target tracking subsystem 204, and the current transducer module (107) spatial position (rx, ry, rz, Φ x, Φ y, Φ z), a record of the position is sent to the 3D image registration reconstruction module 206 and saved for future treatment reference. In some embodiments, the ultrasound system 100 automatically records the trajectory of the arm 106 moving from one location to the next as the operator/clinician moves the transducer module 107 on the patient, even if the operator/clinician does not click the arm 106 on a button.

In some embodiments, the 3D image registration reconstruction module 206 reconstructs the 3D treatment volume (e.g., the 3D image registration reconstruction module 206 in fig. 3) from the robotic arm spatial position control subsystem 205 in conjunction with all the 2D ultrasound images (Ii) acquired from the ultrasound imaging target tracking subsystem 204 and the corresponding transducer module (107) spatial positions (rx, ry, rz, Φ x, Φ y, Φ z). The dose plan calculation timing control module 207 calculates the dose (ultrasound energy and microbubble/drug dose) and delivery time series based on the expected treatment location (Xi, Yi, Zi) within the 3D volume reconstructed from the B-mode selected by all clinicians. And delivering ultrasound energy to register the treatment volume from the transducer module position and the 3D reconstruction as a current treatment position (Xj, Yj, Zj). Δ Xi, Δ Yi, and Δ Zi are the expected treatment position displacements due to spatial motion compensation. In some embodiments, the range of movement distances relative to the intended treatment location (any of Δ Xi, Δ Yi, Δ Zi) that can be tracked and calculated by the tracking algorithm is in any range of about 0mm to about 20mm, about 10mm to about 20mm, about 0mm to about 10mm, about 5mm to about 10mm, about 0mm to about 5mm, about 0mm to about 2mm, about 0mm to about 1mm, about 0.5mm to about 1mm, about 0mm to about 0.5mm, about 0mm to about 0.1mm, about 0.01mm to about 0.1mm, or about 0.001mm to about 0.01 mm. In some embodiments, the range of movement distances relative to the intended treatment location (any of Δ Xi, Δ Yi, Δ Zi) that can be tracked and calculated by the tracking algorithm is any of about 20mm, about 19mm, about 18mm, about 17mm, about 16mm, about 15mm, about 14mm, about 13mm, about 12mm, about 11mm, about 10mm, about 9mm, about 8mm, about 7mm, about 6mm, about 5mm, about 4mm, about 3mm, about 2mm, about 1mm, about 0.5mm, about 0.1mm, about 0.05mm, about 0.01mm, about 0.001mm, or about 0 mm. In some embodiments, when there is no motion compensation, i.e., the current treatment position overlaps the intended treatment position in all dimensions, then Δ Xi ═ 0, Δ Yi ═ 0, and Δ Zi ═ 0. In some embodiments, the ultrasound system automatically moves the transducer module 107 to the origin of the desired treatment location, i.e., the clinician/operator selected tumor center location.

In some embodiments, the dose plan calculation timing control module 207 optimizes treatment locations and provides the most effective treatment plan by adding, subtracting or interpolating treatment locations from the clinician selected ultrasound images. In some embodiments, the dose plan calculation timing control module 207 determines whether the treatment locations are too close to other critical organs based on the 3D reconstructed volume and whether the number of treatment locations is sufficient to cover the entire cancer volume the images generated by the 3D image registration reconstruction module 206. In some embodiments, the dose plan calculation timing control module 207 suggests one or more new locations for adding therapy based on the size of the tumor.

In some embodiments, the spatial position of the transducer module 107 including the therapy transducer 219 is calculated and controlled by dose plan calculations and by delivery via a time series control module (e.g., the dose plan calculation timing control module 207 in fig. 3). The robotic arm 106 and transducer module 107 move from one spatial location to another for scan path validation after treatment planning, without turning on any ultrasound treatment energy during scan path operation.

In some embodiments, the desired 3D treatment volume is segmented from pre-recorded 3D CT or MRI images of the patient and used for dose plan optimization. The 3D reconstructed ultrasound treatment volume from the 3D image registration reconstruction module 206 is registered with the patient's 3DCT or MRI treatment volume using a 3D point cloud registration algorithm in module 206. The treatment region is then determined by dose planning calculation of the dose, which is overlaid on the 3D reconstructed volumetric image registered with the pre-existing 3D CT or MRI image of the treatment region by a dose planning calculation timing control module 207 in order to verify and optimize the treatment position (see e.g. fig. 8).

In some embodiments, the ultrasound therapy subsystem 202 turns on therapy energy delivery (e.g., output from the therapy transducer 219) while cavitation conditions are detected via the transducer module 107 and monitored with the cavitation therapy monitoring subsystem 203. The dose of therapeutic ultrasound energy delivery is also detected by the cavitation therapy monitoring subsystem 203 using received broadband noise transmit signal quantification from the broadband receive sensor 218 to detect inertial cavitation and using subharmonic transmit signals to monitor steady state cavitation. The monitoring and quantification outputs are transmitted to the computing unit real time controller subunit 200 and the cavitation state of the target is evaluated by the computing unit within the subsystem 200. Depending on whether the cavitation status is below steady-state cavitation (low), steady-state cavitation (yes), or above inertial cavitation (high; see cavitation status determination chart in fig. 3), the dose compensation signal is sent to the dose plan calculation timing control module 207 where the therapeutic ultrasound intensity is adjusted to increase, remain the same, or decrease depending on the cavitation status until steady-state cavitation is consistently detected by the cavitation therapy monitoring subsystem 203.

In some embodiments, the system 100 described herein initiates treatment and automatically moves the transducer module to deliver therapeutic ultrasound energy from one spatial location to another spatial location at a defined desired treatment location after dosage and treatment planning.

In some embodiments, the system 100 described herein captures post-treatment B-mode images at each treatment location for comparison with images obtained before treatment and images that serve as future references.

In some embodiments, the system 100 described herein further includes an interface through which remote control of the non-invasive ultrasound system is provided by controlling the movement of the robotic arm 106, which also provides for the transmission of images and data.

In some embodiments, a Cavitation Dose Metric (CDM) is calculated within the dose plan calculation timing control module 207 and is used to indicate the intensity of cavitation effects, which is related to the effective ultrasound treatment dose. It monitors the safety and efficacy of treatment in relation to the extent of drug penetration for each patient, and thus, the drug uptake by cancer cells. The CDM combines the steady-state cavitation metric and the inertial cavitation metric, and calculates a steady-state cavitation threshold and an inertial cavitation threshold based on power spectrum calculations of the RF signals monitored during processing. The steady-state cavitation metric is calculated by integrating the amplitude of the RF signal spectrum over the ultraharmonics and subharmonics within a particular bandwidth (e.g., 100kHz-600kHz) around the harmonics. The inertial cavitation metric is an integral of the Root Mean Square (RMS) amplitude of the broadband emission detected by the broadband reception sensor 218. The steady state and inertial cavitation thresholds were reached when the steady state and inertial cavitation metrics were 3dB higher during treatment. Before treatment, the inertial cavitation threshold is above steady state cavitation. If the treatment is accompanied by microbubbles, the steady State Cavitation Threshold (SCT) should be exceeded to enhance drug turnover. And the treatment should be set below the Inertial Cavitation Threshold (ICT) to avoid tissue damage. If microbubbles are not used for treatment, the inertial cavitation threshold should be set to be exceeded to maintain the cavitation effect. The cavitation occurrence region is defined as the sum of all spatial location points on the B-mode image where the cavitation energy level is above a defined initial or steady state cavitation threshold. When drug delivery utilizes a steady state cavitation effect, if CDM is below SCT, the cavitation condition is considered low and the ultrasound intensity should be increased until CDM is greater than SCT but less than SCT plus 2 dB. When moderate tissue destruction is induced using inertial cavitation effects, the ultrasound intensity should remain constant if CDM reaches ICT and remains within ICT plus 2dB, and should be reduced by control of dose plan calculation 207 if CDM exceeds ICT by more than 2 dB.

In some embodiments, the treatment plan and current treatment status may be displayed on the treatment monitoring display 105, which includes the cavitation image and intensity, the current treatment position and the expected treatment position as determined by dose plan calculations within the reconstructed 3D, the treatment volume, and CDM conditions within the current treatment plane, among other things, an exemplary display is given in fig. 8. As shown in fig. 8, the expected treatment location within the region (i.e., the optimized treatment region determined by the dose plan calculation), the complete treatment region ("treatment region") and the location of cavitation in the cross-section of the 3D treatment region are overlaid on the ultrasound B-mode image over the conventional treatment region. And monitoring the cavitation intensity in real time, displaying the cavitation intensity on the upper right side of the display, and displaying a steady-state cavitation threshold value and an initial cavitation threshold value. The treatment monitoring display 105 also shows the optimized treatment region determined by the dose plan calculations overlaid within the 3D reconstructed volumetric image from the 3D image registration reconstruction module 206. Treatment efficacy is monitored in real time by Cavitation Dose Measurement (CDM) and displayed to the lower right of treatment monitoring display 105. The cavitation position and intensity are displayed in real time within the intended treatment area and the treatment area is superimposed on the B-mode image, providing the clinician with detailed information of the real-time treatment plan and treatment status, thereby greatly improving treatment safety. If cavitation is detected to occur outside the intended treatment area, the treatment should be stopped and the position of the transducer module 107 should be readjusted. If the treatment is found to be completed at one treatment location, the transducer module 107 should be moved to the next desired treatment location, either manually by the clinician or as determined by the ultrasound engine control system 103.

In some embodiments, the imaging from the treatment monitoring display 105 is a 1D plot over time to show real-time cavitation status. In some embodiments, the imaging from the treatment monitoring display 105 is a 2D map of the cavitation signal (e.g., color-coded cavitation intensity) superimposed on the B-mode image to show the location and intensity of cavitation occurrence.

Fig. 1A-1B illustrate an exemplary system 100 for enhancing medical treatment using ultrasound by applying ultrasonic energy to the medical treatment through a robotic arm 106. Configured to deliver defined ultrasound energy to a target treatment area, such as the upper and mid-abdominal regions of a patient's body. For example, the system can target a pancreatic cancer region and surrounding tissue to generate cavitation within the patient's pancreas. The system may also be used to deliver focused ultrasound energy to other tissues or organs of the patient. The system may be configured to enhance treatment of different tissues or organs in conjunction with various treatment methods and/or ultrasound-mediated therapeutic agents, depending on the location and depth of the target tissue in the body.

As shown in fig. 1 and 2, as shown in fig. 1A-1B, the system 100 includes an ultrasound engine control system 103, an ultrasound imaging display 104, a therapy monitoring display 105 (hereinafter also referred to as a "therapy monitoring display"), a robotic arm 106, a transducer module 107, an ultrasound engine control system 103, and a drug delivery unit. The ultrasound engine control system 103 serves as a controller for the entire ultrasound system: it activates the therapy transducer 219, processes the cavitation signal detected by the transducer module 107, and modulates the transducer positioning mechanism via the robotic arm 106. Two user interface ultrasound imaging displays 104 and a treatment monitoring display 105 are configured to monitor, control, and synchronize ultrasound imaging, treatment, drug delivery, and movement of the robotic arm 106. The robotic arm 106 facilitates positioning of the transducer module 107 on the patient's body 101. Fig. 1A-1B illustrate two exemplary system configurations, with the robotic arm 106 having different mounting orientations relative to the clinician/operator and the patient 101. In addition to the transducer module 107, the robotic arm 106 may also be used for placement on a patient by the patient via other medical tools. During treatment, a tool, such as a camera on top of the transducer module 107, is monitored.

As shown in fig. 1A-1B, a patient 101 is treated on a hospital bed 102. The clinician moves the transducer module 107 configured at the distal end of the robotic arm 106 to a treatment area, such as the abdomen of a patient. An ultrasound imaging display 104 displays the abdominal structure of the patient using ultrasound B-mode images. The clinician/operator locates the desired treatment region within the patient by ultrasound imaging (e.g., location of a tumor or size of a lesion) displayed on the treatment monitoring display 105. The ultrasound engine control system 103 reconstructs a 3D volumetric image using the B-mode images or received signals, and the spatial location of the captured images, and then develops a treatment plan for display on the treatment monitoring display 105. The robotic arm 106 moves the transducer module 107 to target a first desired treatment location and then applies treatment according to the treatment plan. The ultrasound energy generated from the transducer module 107 is adjusted until a cavitation effect is induced in the target region during treatment. The treatment monitoring display 105 displays cavitation energy and location information in real time. The ultrasound energy delivered to the target is adjusted to a level defined in the treatment plan developed by the ultrasound engine control system 103 by adjusting ultrasound system control parameters based on detection signals from cavitation monitoring, and the position of the ultrasound energy delivery is also adjusted to follow the movement of the treatment site due to patient breathing by using the robotic arm 106 and spatial position tracking based on ultrasound imaging. After each position treatment, the robotic arm 106 moves to the next treatment position according to the treatment plan until the defined treatment volume is completely covered.

Fig. 2 depicts the major components of the ultrasound engine control system 103, and its coordination with the other components of the ultrasound system 100. In some embodiments, the ultrasound engine control system 103 includes a computing unit real-time controller 200, a drug delivery control subsystem 201, an ultrasound therapy subsystem 202, a cavitation therapy monitoring subsystem 203, an ultrasound imaging target tracking subsystem 204, and a robotic arm spatial position control subsystem 205.

The computational unit real-time controller 200 includes a Central Processing Unit (CPU), a 3D image registration reconstruction module 206, and a dose plan calculation delivery timing control module 207. In some embodiments, the ultrasound engine control system 103 further comprises a power source (not shown in fig. 2). In some embodiments, the ultrasound engine control system 103 also includes other standard system hardware and software, such as an operating system, a plurality of Radio Frequency (RF) amplifiers, display drivers, interconnection cables to the transducer module 107, a system display, a keyboard.

The robotic arm 106 is used for six-axis displacement control, modulated by a dose plan calculation time series control module 207, a treatment volume and robotic arm spatial position control subsystem 205. Having a real single board computer time controller board, such as an FPGA board (not shown in figure 2), would together provide software within the ultrasound engine control system 103 to receive dose information, cavitation information and mechanical position information and send to the computing unit real time controller 200. Computational unit real-time controller 200 performs operations to monitor cavitation, calculate treatment dosage, process and adjust ultrasound energy parameters, and send feedback to each subsystem of the module. The drug delivery control subsystem 201 sends signals to the drug delivery unit 108, the ultrasound therapy subsystem 202 and the cavitation therapy monitoring subsystem 203 coordinate and control the transducer module 107. The signals/information obtained by the transducer module 107 are sent to the ultrasound imaging target tracking subsystem 204 for imaging display and target tracking purposes.

Fig. 3 depicts an exemplary functional diagram of the ultrasound engine control system 103 and its coordination with other components of the system 100. The ultrasound engine control system 103 includes a computing unit real-time controller 200 interconnected with drug delivery, a control subsystem 201, an ultrasound therapy subsystem 202, a cavitation therapy monitoring subsystem 203, an ultrasound imaging target tracking subsystem 204, and a robotic arm spatial position control subsystem 205.

The calculation unit real-time controller 200 includes a 3D image registration reconstruction module 206 and a dose plan calculation timing control module 207. The ultrasound engine control system 103 synchronizes the motion and function of the robotic arm 106, the transducer module 107 and the drug delivery unit 108.

In this example, in one embodiment, the ultrasound engine control system 103 includes not only conventionally functioning ultrasound imaging systems, such as imaging by the ultrasound imaging target tracking subsystem 204 and some limited treatment power output by the ultrasound therapy subsystem 202, but also several unique features for medical treatment, such as drug delivery control subsystem 201 delivery control for drugs, cavitation therapy monitoring subsystem 203 for cavitation monitoring, mechanical arm spatial position control subsystem 205 for mechanical arm 106 motion control, 3D image registration reconstruction module 206 for 3D image registration and reconstruction, dose plan calculation timing control module 207 for dose planning and timing control, and other computational and control functions, the transducer module 107 including the imaging transducer 231 is configured with 6D motion capability at the distal end of the mechanical arm 106, wherein, the robotic arm 106 is controlled based on signals processed and output from the computing unit real-time controller 200 and software within the host system, the robotic arm 106 moving the transducer module 107 toward or away from the patient's body and providing 3D spatial motion capability, coverage therapy volume. The intended treatment location within the area is detected by the imaging transducer 231 within the transducer module 107. The pulse-echo signals acquired by the imaging transducer 231 are processed by the ultrasound imaging target tracking subsystem 204 into a B-mode ultrasound image to determine that the desired treatment position (Xi, Yi, Zi) selected by the clinical manual or dose plan control 207 automatically corresponds to the current ultrasound B-mode image. The current treatment position (Xj Yj, Zj) is measured at the coordinates of the imaging transducer 231. The current treatment position may shift due to organ motion from the patient's breathing. At the same time, the acquired image (Ii) is sent to the 3D image registration reconstruction module 206 along with the corresponding spatial locations (rx, ry, rz, Φ x, Φ y, Φ z) of the transducer module 107 to reconstruct the initial image. The 3D volume image, which determines the 3D treatment volume after the initial 3D reconstruction of the B-mode image, may also reconstruct a spatial motion profile of the treatment location (e.g., tumor) within the 3D volume image. The expected treatment positions and their distances relative to each other are optimized by dose planning calculations. The current treatment location along with the cavitation state is processed by the dose plan calculation timing control module 207 to generate a new delivery time sequence and motion compensated control, e.g., for the ultrasound therapy subsystem 202 to adjust the ultrasound energy dose and delivery time, for the drug delivery control subsystem 201 to adjust the delivery time and dose of the drugs/microbubbles, and for the robotic arm spatial position control subsystem 205 to calculate the delivery time to perform the changes between the desired and current treatment locations and motion compensate the ultrasound energy and drugs/microbubbles. In this manner, both the ultrasound energy and the controlled delivery of microbubbles/therapeutic agents to all treatment sites within the patient's body can be simultaneously satisfied and monitored. This method of treatment provides a great improvement in the safety and efficacy of drug delivery for cancer therapy.

In some embodiments, a real-time treatment position compensation program (such as a real-time treatment position compensation program established within the computing unit real-time controller subsystem 200) is provided that computes spatial positions (rxj, ryj, rzj) and motion compensation (Φ x, Φ y, Φ z) for the transducer modules based on the respective treatment positions (Xj, Yj, Zj) and spatial motion (Δ Xi, Δ Yi, Δ Zi) of the treatment positions relative to the intended treatment position (Xi, Δ Yi, Δ Zi) is mapped using real-time ultrasound images (images [ Ixj, Iyj ] of the current treatment position, images [ Ixi, Iyi ] relative to the intended treatment position.

In some embodiments, the program may input a series of base values:

1) the intended treatment position (Xi, Yi, Zi);

2) a corresponding registered B-mode image (Ixi, Iyi) of the intended treatment location;

3) when a B-mode image is captured (rxi, ryi, rzi, Φ x, Φ y, Φ z), the corresponding spatial location of the transducer module.

For example, the basis values are input for various spatial treatment positions in order to cover the entire intended treatment volume of the tumor. Within the cross-section of the intended treatment volume, there may be several intended treatment locations. In some embodiments, the program automatically samples the desired treatment locations (Xi, Yi, Zi) during scanning of the desired treatment volume (e.g., tumor) and aligns each desired treatment location (Xi, Yi, Zi) with a respective B-value. A mode image (Ixi, Iyi) of the intended treatment location, and a corresponding spatial location of the transducer module when the B-mode image was captured [ (rxi, ryi, rzi), Φ x, Φ y, Φ z ]. During treatment, the program compares the B-mode image of the real-time treatment position ([1Xj, Iyj ]) with the B-mode image of the intended treatment position (Ixi, Iyi), which reflects the real-time (current) treatment position (Xj, Yj, Zj), and then the spatial motion (Δ Xi, Δ Yi, Δ Zi) of the treatment position relative to the intended treatment position (Xi, Yi, Zi) can be calculated by the program according to the formula: Δ Xi ═ Xj-Xi, Δ Yi ═ Yj-Yi, Δ Zi ═ Zj-Zi.

In some embodiments, when there is no spatial motion of the motion compensated/treatment position, i.e., the current treatment position overlaps the intended treatment position in all dimensions, Δ Xi is 0, Δ Yi is 0, and Δ Zi is 0. The spatial position of the transducer module will remain aimed at the intended treatment location until the treatment is compiled. The robotic arm 106 then moves the transducer to the next predetermined treatment position. Finally, the program calculates the real-time spatial position of the transducer module (i.e., the position to which the transducer module should move due to patient/organ motion) according to the following formula: Δ P ═ P (xj, yj, zj) -P (xi, yi, zi).

In some embodiments, a real-time treatment dose compensation program (e.g., a real-time treatment dose compensation program established within the computational unit real-time controller subsystem 200) is provided that actually calculates the ultrasound/treatment drug dose compensation based on the time of Cavitation Dose Metric (CDM). When the treatment utilizes steady-state cavitation, if CDM is less than SCT, the ultrasound intensity is increased until CDM is in the range of SCT to SCT +2 dB. When CDM is outside this range, the intensity is controlled to drop by dose compensation system 200, otherwise the intensity remains unchanged. When the treatment utilizes inertial cavitation, if CDM is less than ICT, the intensity increases to the ICT to ICT +2dB range. When CDM is out of range, the strength is reduced using a lower strength setting. When the cavitation map is overlaid on the B-mode image, the real-time (current) treatment position (Xj, Yj, Zj) is displayed as being offset from the intended treatment position (Xi, Yi, Zi) from the B-mode imaging. The distance between the two positions (Δ Xi, Δ Yi, Δ Zi) is adjusted to move the current position to the desired position by the subsystem 200. The adjustments are then translated to the processing module positions.

At the beginning of the treatment session, the therapeutic drug is delivered to the patient's vein by the drug delivery unit 108. In some embodiments, the drug delivery unit 108 includes only the chemotherapy drug delivery unit 211. In some embodiments, the drug delivery unit 108 includes only the ultrasound contrast agent delivery unit 212. In some embodiments, the drug delivery unit 108 includes both a chemotherapy drug delivery unit 211 and an ultrasound contrast agent delivery unit 212. The chemotherapy drug delivery unit 211 and/or the ultrasound contrast agent delivery unit 212 may be in the form of a syringe connected to an automated infusion pump. The automated infusion pumps may be controlled individually or together by the drug delivery control subsystem 201. After the clinician identifies the desired treatment location from the ultrasound images displayed on the ultrasound imaging display 104, ultrasound energy with a determined treatment dose is delivered to the desired treatment location under the control of the ultrasound treatment subsystem 202. Where the dose is calculated and controlled by the dose plan calculation schedule control module 207 (fig. 3). The cavitation therapy monitoring subsystem 203 will monitor the cavitation emission signals from the treatment site and process the received cavitation signals to determine the cavitation status. If steady state cavitation is achieved and the cavitation intensity is within the cavitation threshold, e.g., between the steady state and inertial cavitation thresholds, the cavitation status signal is transmitted to the dose plan calculation timing control module 207, which further instructs the drug delivery control subsystem 201 to maintain the drag dose. However, if cavitation does not occur or cavitation instability does not occur, a cavitation status signal is sent to the dose plan calculation timing control module 207, which instructs the drug delivery control subsystem 201 to stop drug delivery or increase the amount of microbubbles. If the cavitation is too high, a cavitation status signal is sent to the dose plan calculation sequence control module 207 and the dose plan calculation sequence control module 207 instructs the drug delivery control subsystem 201 to stop drug delivery or reduce the amount of microbubbles. During the drug delivery control process described above, the drug delivery control subsystem 201 is also synchronized with the ultrasound therapy subsystem 202 by the control and delivery time series control module 207 of the dose plan calculation. Based on the cavitation status of the signal from cavitation and in the treatment monitoring subsystem 203, the ultrasound energy delivered to the treatment site is adjusted to maintain the desired cavitation status, e.g., steady state cavitation or inertial cavitation, for the desired therapeutic effect.

In some embodiments, the transducer module 107 (see, e.g., fig. 7) includes one or more broadband reception sensors 218 and a therapy transducer 219. In some embodiments, the ultrasound therapy subsystem 202 includes an ultrasound output energy control 213 and an optional signal amplifier 214 (fig. 5). Thus, in some embodiments, when high output acoustic power is required in a clinical application, the power amplifier 214 further amplifies the signal controlling the ultrasonic energy output before sending to the therapy transducer 219. As the delivered ultrasound energy is gradually increased, the cavitation therapy monitoring subsystem 203 monitors the onset of steady-state cavitation based on the signal sent from the broadband reception sensor 218. In some embodiments, the cavitation therapy monitoring subsystem 203 includes a cavitation detection monitoring algorithm 215, an analog-to-digital (a/D) converter 216, and an optional preamplifier 217 (see fig. 6). Upon the occurrence of a cavitation event, the cavitation signal is detected by a broadband receiving sensor 218 within the transducer module 107 and optionally amplified by a preamplifier 217. The detected steady state cavitation signal is converted by the a/D converter 216 and processed by the cavitation detection monitoring algorithm 215, and the processed cavitation signal is sent to the computing unit real time controller 200, which dynamically controls the drug delivery control subsystem 201 and the ultrasound therapy subsystem 202, thereby dynamically adjusting the ultrasound energy output. Steady state cavitation conditions are maintained and drug dose is optimized for delivery to the target during clinical treatment.

Fig. 7A-7B depict two exemplary transducer modules 107 including a frame 230, an imaging transducer 231, a therapy transducer 219, and one or more broadband receiving sensors 218. Fig. 7A depicts an exemplary configuration of the transducer module 107 in which an imaging transducer 231 and a separate therapy transducer 219 are located within the transducer module 107 with a plurality of broadband reception sensors 218 for cavitation monitoring around the imaging transducer 231. Fig. 7B depicts an exemplary configuration of the transducer module 107 in which a single transducer array has integrated functions of imaging, therapy, and cavitation monitoring. The multifunctional transducer array (broadband receiving sensor 218, imaging transducer 231, therapy transducer 219) may be a stand-alone hardware, an off-the-shelf module, or a custom module. The multifunctional transducer array 220 is used for imaging, therapeutic ultrasound energy generation and reception of cavitation signals, which simplifies the construction and implementation of the transducer module 107 in a clinical environment.

Biological effects in the target tissue caused by cavitation can include intense local heating, flow, pitting and cell disruption, depending on the intensity and duration of the delivered ultrasonic energy. In some embodiments, the non-invasive ultrasound systems described herein may generate a localized hot zone around a target (e.g., a tumor) when delivering high power and/or tightly focused ultrasound energy to the target. In some embodiments, the ultrasound energy is delivered in combination with a heat-sensitive therapeutic agent. In some embodiments, the heat-sensitive therapeutic agent is not released until activated by ultrasonic energy. In some embodiments, the thermosensitive therapeutic agent is selected from lysolipid thermosensitive liposomes, polylactides, polyglycolides, ethylene vinyl acetate, poly (lactide-co-glycolide, poly (N-isopropylacrylamide), poloxamers, and chitosan.

The system 100 described herein is compatible with a variety of therapeutic agents (and pharmaceutical formulations thereof). These agents are intended to provide a variety of effects, such as antibiotics, antivirals, chemotherapy, cell repair and gene therapy activities, or a combination of antibiotics, antivirals, chemotherapy, cell repair and gene therapy activities. By way of example and not limitation, classes of deliverable drugs include hydrophilic drugs, lipophilic drugs, liposomes, dendrimers, cyclodextrins, nanoparticles, microspheres, peptides, linear and globular proteins (e.g., up to 80kDa), linear and different molecular weight globular gene therapy drugs, adeno-associated viral gene therapy drugs, and RNA/DNA.

In some embodiments, the systems described herein can deliver one or more chemotherapeutic agents, such as, but not limited to, altrexacin, doxorubicin, addumycin, amsacrine, asparaginase, anthracycline, azacitidine, azathioprine, carmustine injectate, bleomycin sulfate, busulfan, bleomycin, irinotecan hydrochloride, camptothecin, carboplatin, carmustine, rubicin hydrochloride, chlorambucil, cisplatin, cladribine, actinomycin, cytarabine, sarisamide, cyclophosphamide, actinomycin D, docetaxel, doxorubicin, daunorubicin, asparaginase, epirubicin, etoposide, fludarabine, fluorouracil, fodalle, gemcitabine, tobaken, hydroxyurea, daunorubicin, idarubicin, ifosfamide, irinotecan, guanine tablets, oncoclonine, clarithrone, tolazine, enbisine, mercaptopurine, methotrexate, mitomycin, mitoxantrone, mithramycin, mitomycin, mariland, azasporine, vinorelbine, pentostatin, decrepins, vincristine, oxaliplatin, paclitaxel, berlidine, pentostatin, cisplatin, plicamycin, procarbazine, mercaptopurine, leralrexed, taxotere, paclitaxel, teniposide, thioguanine, topotecan, valrubicin, vinblastine, vincristine, vinorelbine, VP-16 and dulcite. In some embodiments, the therapeutic agent delivered by the systems described herein is involved in immunotherapy. For example, in some embodiments, the therapeutic agent is an antibody, such as an immune checkpoint inhibitor, including but not limited to anti-PD-1 Ab, anti-PD-L1 Ab, anti-PD-L2 Ab, anti-CTLA-4 Ab, anti-TIGIT Ab.

The system 100 described herein is compatible with a variety of ultrasound contrast agents, such as gas-filled vesicles, gas-filled liposomes, and the like.

The ultrasound contrast agent may be configured to increase contrast in an ultrasound image of the subject. An increase in contrast means that the difference in image intensity between adjacent tissues visualized by ultrasound is enhanced. For example, differences in image intensity may be enhanced by using one or more sets of imaging parameters. In certain embodiments, the ultrasound contrast agent comprises a balloon (GV), e.g., a plurality of balloons. In certain embodiments, the balloon is a genetically encoded balloon. For example, the gas vesicles may be microbially derived, e.g., bacterially derived, gas vesicles formed from bacteria, e.g., photosynthetic bacteria (e.g., cyanobacteria), or the gas vesicles may be archaebacterially derived gas vesicles formed from archaea (e.g., halophiles).

In certain embodiments, the balloon is substantially spherical. In some cases, the balloon is elliptical. Other shapes are possible depending on the type of bacteria from which the balloon is derived. For example, the bubble may be cylindrical, or may have a cylindrical central portion, the ends of which are tapered, or may be football shaped, or the like.

In certain embodiments, the balloon has dimensions on the nanometer scale, with precise dimensions and shapes that vary between genetic hosts. Nanoscale means that the average size of the balloon is 1000nm or less, such as 900nm or less, including 800nm or less, or 700nm or less, or 600nm or less, or 500nm or less, or 400nm or less, or 300nm or less, or 250nm or less, or 200nm or less, or 150nm or less, or 100nm or less, or 75nm or less, or 50nm or less, or 25nm or less, or 10nm or less. For example, the average diameter of the bubbles may be from 10nm to 1000nm, such as from 25nm to 500nm, including from 50nm to 250nm, or from 100nm to 250 nm. "average" means the arithmetic mean.

In some embodiments, the ultrasound contrast agent is a microbubble, such as an FDA approved microbubble Optison, Definity, Lumanson. These microbubbles comprise a gaseous core (e.g., perfluorocarbon) encapsulated by a shell, ranging in size from 1-4 μm, which is smaller than the size of red blood cells, allowing them to circulate freely within the vasculature.

In some embodiments, the balloon/microvesicles are conjugated to a targeting molecule (e.g., a polypeptide, an antibody or a ligand/receptor) to provide a higher affinity of the balloon/microvesicle to the target region (e.g., a tumor). For example, in some embodiments, the vesicles/microvesicles are conjugated to an antibody that specifically recognizes a tumor antigen of a target tumor for therapy. In some embodiments, the vesicles/microvesicles are conjugated to targeting molecules (e.g., anti-VEGFR antibodies or VEGF polypeptides) that specifically recognize endothelial biomarkers (e.g., VEGFR) associated with tumor angiogenesis or inflammation.

Following a general medical diagnostic procedure, the patient is diagnosed with pancreatic cancer. The following clinical procedures apply before, during and after treatment:

1) patients were evaluated and met the following patient selection criteria: a) the patient has undergone CT (computed tomography) or MRI (magnetic resonance imaging) to verify the stage, location, etc. of pancreatic cancer; b) the patient has no cardiovascular disease or other disease affecting the duration of treatment (about one hour); c) the patient was evaluated by ultrasound imaging and pancreatic cancer was identified by the imaging method.

2) After the patient lies on the treatment couch, the clinician/operator adjusts the system position to ensure that the robotic arm 106 is closest to the patient's couch and that the transducer module 107 attached at the end of the robotic arm 106 can reach the treatment area patient.

3) The ultrasound imaging display 104 and the therapy monitoring display 105 are adjusted for better visualization by the clinician while scanning the patient.

4) Locking the wheels of the system.

5) An ultrasound gel is applied over the treatment area and the transducer module 107 is used to identify the central tumor area. The transducer module 107 is moved to different positions to scan different regions or aspects of the tumor. Each time the tumor region is visualized, the clinician clicks a button on the robotic arm 106 to record the desired treatment location and save the image for future treatment planning.

6) The system records the initial treatment location, which is the clinician-determined tumor center. The initial position is set as the origin of the treatment. As the clinician moves the transducer module 107, the system records the trajectory of the robotic arm (and thus the distally connected transducer module) as the clinician clicks on the button to move from one spatial location to the next.

7) The system combines all ultrasound images selected by the clinician and the corresponding spatial positions of the transducer module 107 attached to the distal end of the robotic arm 106 to reconstruct a 3D volumetric image with a 3D image registration reconstruction module 206, where the images are recorded by the ultrasound imaging target tracking subsystem 204 and the corresponding spatial positions of the transducer modules are recorded by the robotic arm 106 spatial position control subsystem 205 when the images are captured. Once the 3D volumetric image registration and reconstruction module 206 is reconstructed within the 3D image, the tumor region will be identified and segmented in 3D space. The desired treatment locations corresponding to the ultrasound images are then processed by the dose plan calculation timing control module 207, wherein the desired treatment locations are further optimized to provide the most efficient treatment plan, i.e., by adding, subtracting or interpolating further treatment locations, e.g., determining whether the treatment locations are too close to each other or critical organs, and whether the number of treatment locations is sufficient to cover the cancer volume. The dose plan calculation timing control module 207 also suggests one or more new treatment positions based on the size of the tumor. Once the cancer treatment region and treatment plan corresponding to the 3D reconstructed volumetric image are optimized by the dose plan calculation timing control module 207, the dose plan calculation timing control module 207 will generate and send a set of delivery time series of ultrasound energy to the ultrasound treatment subsystem 202 and a set of delivery time series of microbubbles and/or therapeutic drugs to the drug delivery control subsystem 201, the dose plan calculation timing control module 207 will also move to a set of target treatment positions to cover the optimized treatment region, translating the translation module into the spatial position of the transducer module. The target treatment location on the reconstructed image converted to the transducer module location (rxi, ryi, rzi, Φ x, Φ y, Φ z) is compensated by tissue motion. The current treatment position is updated by the robotic arm spatial position control subsystem 205 to move the transducer module through the robotic arm 106.

8) The expected treatment position calculated and optimized by the dose plan calculation timing control module 207 before the actual treatment starts is verified by moving the robotic arm 106 from one position to another based on the dose and treatment plan, which includes the time series of delivery of ultrasound energy and microbubbles and/or therapeutic drugs, and using the robotic arm 106 spatial position calculated and generated from step 7) to optimize the treatment position without turning on the treatment power. The operator will verify the optimal treatment position determined by the dose and treatment plan overlaid on the B-mode ultrasound image displayed on the ultrasound imaging display 104 and check if there is any disturbance in the robot arm motion during the powerless treatment procedure.

9) The operator can display the optimized treatment positions generated by the dose planning calculations on the treatment monitoring display 105 and deliver the time series control module 207 by overlaying them on the 3D reconstructed volume images generated by the 3D image registration and reconstruction module while displaying the 3D CT or MRI images side by side on the 3D reconstructed volume images on the ultrasound imaging display 104 in order to verify and optimize the treatment positions.

10) The clinician validates the treatment plan and the motion of the transducer module 107. If the treatment position is not satisfied, returning to the step 5) and repeating.

11) Once the treatment plan and transducer module motion are approved, the system obtains baseline B-mode images.

12) Intravenous administration of the microbubble-drug conjugate was initiated following the guidelines of the EU UCA administration procedure.

13) The system automatically moves the transducer module 107 to the beginning of the treatment, i.e. the center of the cancer treatment.

14) The therapy energy delivery is turned on to detect microbubble cavitation while the transducer module 107 is in use. The inertial cavitation and the subharmonic emission are quantified through broadband noise emission to achieve stable cavitation, and if the dosage is insufficient, the intensity is adjusted until the system detects the stable cavitation all the time.

15) During treatment, the ultrasound system automatically moves the transducer module 107 including the treatment transducer 219 from one position to another using robotic arms to deliver therapeutic ultrasound energy at a defined target region after dosage and treatment planning.

16) The system automatically tracks patient motion using a tracking algorithm (described herein).

17) The treatment is completed.

18) Post-treatment B-mode images are obtained from each treatment location and compared to pre-treatment images for future reference.

The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and inventive features disclosed herein.

Claims

1. A system for enhancing medical treatment using ultrasound, comprising:

a robotic arm that is free to move in space;

a transducer module configured at the tip of the robotic arm to move along the targets, wherein the transducer module is capable of delivering therapeutic ultrasound energy at the location of the targets, detecting the location of the targets, obtaining ultrasound imaging information of the targets, and monitoring the cavitation status of each of the targets;

2. The system of claim 1, wherein the transducer module comprises separate transducer elements for each function, including a therapy transducer, an imaging transducer, and one or more broadband receiving sensors.

3. The system of claim 1, wherein the transducer module comprises a single multi-functional transducer array integrated with the functions of transmitting therapeutic ultrasound energy, detecting a target location, and monitoring cavitation conditions from respective transducer elements.

4. The system of claim 2 or 3, wherein the transducer module further comprises a frame surrounding the transducer elements.

5. The system of claim 1, wherein the transducer module is removably mounted on the robotic arm.

6. The system of claim 1, wherein the robotic arm has six degrees of freedom of motion.

7. The system of claim 1, wherein the transducer module sends signals to an ultrasound engine control system via a cable line or wirelessly.

8. The system of claim 1, wherein the number of robotic arms is 2, one of said robotic arms having said therapy transducer mounted thereon, the other of said robotic arms having said imaging sensor and 1 or more of said broadband receiving transducers mounted thereon.

9. The system of claim 1, wherein the number of said robotic arms is 3, one of said robotic arms having said therapy transducer mounted thereon, one of said robotic arms having said imaging transducer mounted thereon, the other of said robotic arms having 1 or more broadband receiving transducers mounted thereon.

10. The system of claim 1, further comprising an interface through which movement of the robotic arm is controlled to enable remote control of the system, the interface capable of providing image data to a location of the remote control.

11. The system of claim 1, wherein the anatomical ultrasound imaging is a 3D reconstructed image from a B-mode image or a plurality of ultrasound images.

12. The system of claim 1, wherein the imaging from the therapy monitoring display is a 1D map showing the cavitation status over time, and/or a 2D map of the cavitation status overlaid on the anatomical ultrasound imaging.

13. The system of claim 2, wherein the therapy transducer is capable of generating pulses for inducing steady-state or inertial cavitation with or without the ultrasound contrast agent.

14. The system of claim 2, wherein the imaging transducer receives pulses for the anatomical ultrasound imaging.

15. The system of claim 2, wherein the broadband reception sensor receives pulses for cavitation monitoring or cavitation imaging.

16. The system of any one of claims 1-3, 5-15, wherein the ultrasound engine control system further comprises a robotic arm spatial position control subsystem under control of a dose plan calculation sequence control module contained within the computational unit real time controller to control spatial movement of the robotic arm.

17. The system of claim 16, wherein the ultrasound engine control system further comprises an ultrasound imaging target tracking subsystem, wherein the ultrasound imaging target tracking subsystem receives the anatomical ultrasound imaging from the transducer module of each target location and transmits to the computing unit real-time controller.

18. The system of claim 16, wherein the computational unit real-time controller comprises a 3D image registration reconstruction module and the dose plan calculation delivery timing control module.

19. The system of claim 18, wherein the 3D image registration reconstruction module reconstructs a 3D volumetric image of the target using ultrasound imaging of each target location and corresponding spatial location of the transducer module.

20. The system of claim 19 wherein the dose plan calculation delivery timing control module processes target locations of the targets and 3D volumetric images and sends motion compensation signals to the robotic arm spatial location control subsystem for motion compensation at each of the target locations.

21. The system of claim 19 or 20, wherein the ultrasound engine control system further comprises a cavitation therapy monitoring subsystem to provide real-time monitoring of cavitation status as an input to the dose plan calculation delivery timing control module to generate a dose compensation plan and delivery time sequence, wherein the cavitation therapy monitoring subsystem receives cavitation status signals from the transducer module at each of the target locations.

22. The system of claim 21 wherein the dose compensation planned delivery time series is generated by overlaying a cavitation state input for each of the target locations onto ultrasound imaging for each of the target locations.

23. The system of claim 21, wherein the ultrasound engine control system further comprises an ultrasound therapy subsystem, wherein the ultrasound therapy subsystem controls the transducer module to deliver therapeutic ultrasound energy.

24. The system of claim 21, wherein the ultrasound engine control system comprises a drug delivery control subsystem, wherein the drug delivery control subsystem controls the drug delivery unit to deliver the therapeutic agent and/or the ultrasound contrast agent.

25. The system of any one of claims 22-24, wherein the dose compensation plan and the delivery time sequence generated from the dose plan calculation delivery timing control module instruct the ultrasound therapy subsystem to adjust the dose and delivery time of therapeutic ultrasound and instruct the drug delivery control subsystem to adjust the dose and delivery time of the therapeutic agent and/or the ultrasound contrast agent.